The present invention is in the field of the prevention and treatment of cancer. More specifically, this invention relates to the use of 5-lipoxygenase inhibitors and PPAR ligands or derivatives thereof in preventing and treating cancer.
The lifetime risk of breast cancer in American women is higher than for any other malignancy (1). A variety of metabolic and hormonal factors, including dietary fat, are postulated to have a promotional effect on the progression of breast cancer, but how these factors contribute to the pathogenesis of the disease process is not understood (2-4). Growth factors can function as survival factors and have been reported to inhibit apoptosis (5-7). Insulin-like growth factor-1(IGF-1) is an important growth factor for breast cancer. Activation of the IGF-type 1 receptor (IGF-R), possibly through the action of phosphatidylinositol 3-kinase has been suggested to be a critical tumor promotion and survival factor (8-13). Previously, the over-expression of IGF-R and its ligand were reported as conserved features of both breast and lung cancer (14). Blocking the 5-LO pathway of arachidonic acid (AA) metabolism in lung cancer (15) was reported to neutralize IGF-1-dependent growth stimulation and survival effects.
The AA metabolizing enzymes are emerging as significant mediators of growth stimulation for epithelial cells. Earashi and Noguchi suggested that AA metabolism may play a significant role in mammary carcinogenesis through oxidative processes (16, 17), and Przyipiak and co-workers evaluated the effects of 5-LO on the proliferation of MCF-7 cells (18). AA can be metabolized either by the COX or the LO pathways and knowledge about the enzymes responsible for both metabolic routes is rapidly increasing (19-21). As part of a general epithelial survey, the relative frequency of expression of five AA metabolizing enzymes and FLAP in breast cancer cells was established (22). Biologically active products of the 5-LO pathway include 5-HETE and leukotrienes, which contribute to the inflammatory process in a variety of diseases. A number of pharmacological antagonists for the AA pathways are available which act by different mechanisms. The regulation of 5-LO products can be achieved either by direct inhibition of the enzyme such as with the competitive inhibitor AA 861, Zileuton or by the phenol redox inhibitor, NDGA. In addition there exists another class of selective 5-LO inhibitors, MK 886 and MK 591, which are thought to inhibit indirectly by interacting with FLAP and interfering with the presentation of AA to the 5-LO enzyme at the nuclear envelope membrane (20, 23).
There have been reports regarding the mechanistic basis of the anti-proliferative effect of the FLAP inhibitor (26). Induction of differentiation and apoptosis in cancer cells can also occur through the action of other oxidation products of AA. The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor subfamily of transcription factors. The PPARs were originally identified as orphan receptors, without known ligands, but were named for their ability to mediate the pleiotropic effects of fatty acid peroxisome proliferators. PPARs form heterodimers with other members of the nuclear hormone receptor superfamily and these heterodimers regulate the transcription of various genes. There are 3 related types of PPARs, PPARxcex1, PPARxcex4, and two isoforms of PPARxcex3.
Further, PPARs are activated by long chain fatty acids and synthetic ligands, which regulate lipid metabolism and have been further shown to be expressed in breast cancer cells (27). More specifically, elevated expression of PPARxcex3 has been demonstrated in human primary and metastatic breast adenocarcinomas (27) and in Alzheimer""s disease brains (28) while allelic variants have been reported in sporadic colon cancers (29). The pharmacological modulation of PPARxcex3 expression and/or function may therefore be an appropriate point of therapeutic intervention in pathological conditions.
The present invention generally relates to the use of lipoxygenase inhibitors and PPAR ligands in therapeutic applications, in particular to the prevention and treatment of epithelial cell-derived cancers.
The present invention also provides a method for treating an epithelial cell-derived cancer in a subject in need of such treatment which comprises administering to the subject an amount of an inhibitor of a 5-lipoxygenase enzymatic function and a PPAR ligand effective to treat the epithelial cell-derived cancer.
It is also an object of the present invention to provide a method for preventing an epithelial cell-derived cancer in a subject in need of such prevention which comprises administering to the subject an inhibitor of a 5- lipoxygenase enzymatic function and a PPAR ligand effective to prevent the epithelial cell-derived cancer.
It is yet another object of the invention to provide a method for preventing an epithelial cell-derived cancer in a subject in need of such prevention which comprises administering to the subject in need thereof, an amount of an inhibitor of an enzyme that metabolizes arachidonic acid and a molecule subject to transcriptional regulation by binding of RXR heterodimers or variants thereof effective to prevent an epithelial cell-derived cancer.
It is yet another object of the invention to provide a method for treating an epithelial cell-derived cancer in a subject in need of such prevention which comprises administering to the subject in need thereof, an amount of an inhibitor of an enzyme that metabolizes arachidonic acid and a molecule subject to transcriptional regulation by binding of RXR heterodimers or variants thereof effective to treat an epithelial cell-derived cancer.
It is yet another object of this invention to provide pharmaceutical compositions comprising a 5-lipoxygenase inhibitor, PPAR ligand, or derivatives thereof, for the methods described herein.